Pancreatic Cell Fate: To be or not to be
Every single cell in the body contains the same genetic information. However, different types of cells activate distinct sets of genes at different times and locations, which allows them to carry out their precise roles. How do cells achieve this?
The answer lies in a specific structure called chromatin, which is formed of nucleosome units, in which a defined amount of DNA is wrapped around a core of histone proteins. To activate a specific gene, the chromatin first needs to be remodeled to provide access to the transcription machinery (Strahl and Allis, 2000). This process is firmly controlled by chromatin remodeling proteins, which disrupt the tight contact between DNA and histones, and mobilize the nucleosomes to reveal the ‘hidden’ genes (Owen-Hughes, 2003; Bossen et al., 2015).
Failures in the chromatin remodeling machinery can severely hamper the function of a cell, or worse, foster malignant transformations that can lead to cancer (Feinberg et al., 2016; Plass et al., 2013; Wilson and Roberts, 2011). This affects in particular the subunits of the chromatin remodeling complex called SWI/SNF (Kadoch et al., 2013). So far, it has remained unclear how mutations within this structure can lead to the development of tumors. Now, in eLife, Scott Lowe and colleagues from the Memorial Sloan Kettering Cancer Center, the Hannover Medical School and the University of Michigan – including Geulah Livshits as first author – report how a subunit of SWI/SNF, called Arid1a, is involved in the development of pancreatic cancer (Livshits et al., 2018).
Pancreatic cancer is one of the most aggressive types of cancer, with a five-year survival rate of less than 8% (Siegel et al., 2016). Around a quarter of pancreatic cancers contain mutations in the SWI/SNF complex, which are commonly accompanied by mutations in a gene called Kras (Hingorani et al., 2003). Now, Livshits et al. elegantly introduce the subunit Arid1a as a pivotal player in directing the fate of acinar cells – the cells that produce digestive enzymes to help break down food – in the presence of the cancer-causing or oncogenic Kras.
The researchers engineered a mouse model with a Kras mutation that allowed them to turn off Arid1a specifically in the acinar cells by feeding the mice antibiotics. When comparing the pancreas of adult mice with either a Kras mutation only, with deactivated Arid1a only, or with both a Kras mutation and deactivated Arid1a, the results revealed that the consequences of removing Arid1a were determined by the Kras mutation status and the time point of Arid1a depletion in relation to oncogenic activation of Kras (Figure 1).

Schematic illustration of the molecular changes that can alter the identity of acinar cells in the pancreas.
Livshits et al. show that a subunit of the chromatin remodeling protein SWI/SNF, called Arid1a, could contribute to the development of pancreatic cancer. (A) Mice without a Kras mutation and without Arid1a (yellow) did not show any cancer symptoms, suggesting that a lack of Arid1a alone cannot drive the reprogramming of acinar cells (pink). (B) Inactivating Arid1a in the context of a preexisting Kras mutation irreversibly boosts the development of pancreatic cancer (PDAC). (C) Removing Arid1a at the same time as activating the Kras mutation (KrasG12D, red) does not accelerate the formation of precursor lesions that could lead to pancreatic cancer.
Mice without a Kras mutation and without Arid1a did not show any precancerous lesions in their cells, suggesting that the SWI/SNF protein may be dispensable for maintaining the architecture of acinar cells in the absence of oncogenic Kras (Figure 1A). However, inactivating Arid1a in the context of a preexisting Kras mutation significantly accelerated the symptoms of the mice within two weeks: the acinar cells of these mice started to transform into a different phenotype and stopped producing digestive enzymes – instead, they started making other proteins, such as mucins, which are typically found in precancerous or cancerous cells in the pancreas (Figure 1B). Most importantly, these symptoms remained irreversible, even when the antibiotics were removed.
Removing Arid1a in mice embryos at the same time as activating the Kras mutation did not have the same effect (Figure 1C): as the Kras mutation alone eventually leads to formation of pancreatic cancer. The thorough histological and molecular analyses of Livshits et al. demonstrate that a lack of Arid1a can increase the sensitivity of acinar cells to oncogenic signals, leading to the formation of pancreatic cancer. Nevertheless, Arid1a’s contribution to pancreatic carcinogenesis strongly depends on the molecular (mutated Kras) and temporal context (when the Kras mutation occurs).
Due to Arid1a’s ability to influence cell fate, a loss of Arid1a combined with a Kras mutation may therefore severely alter the composition of chromatin. Indeed, when Livshits et al. looked at the chromatin organization, it showed that mice without Arid1a had an abnormal chromatin structure, with genes encoding digestive enzymes being less accessible than in mice with normal Arid1a levels.
Together, the data by Livshits et al. characterize Arid1a as a critical but context-dependent gate keeper of acinar cell fate and pancreatic carcinogenesis. Since chromatin regulatory proteins control reversible processes, they represent promising targets for new therapeutic approaches in cancer treatment. Hence, disentangling the interdependence of the chromatin regulatory protein and context-defining molecular changes in the development of pancreatic cancer and other malignancies, constitutes a difficult but crucial challenge of future studies in the field.
References
-
Epigenetic modulators, modifiers and mediators in cancer aetiology and progressionNature Reviews Genetics 17:284–299.https://doi.org/10.1038/nrg.2016.13
-
Pathways for remodelling chromatinBiochemical Society Transactions 31:893–905.https://doi.org/10.1042/bst0310893
-
Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancerNature Reviews Genetics 14:765–780.https://doi.org/10.1038/nrg3554
-
Cancer statistics, 2016CA: A Cancer Journal for Clinicians 66:7–30.https://doi.org/10.3322/caac.21332
-
SWI/SNF nucleosome remodellers and cancerNature Reviews Cancer 11:481–492.https://doi.org/10.1038/nrc3068
Article and author information
Author details
Publication history
Copyright
© 2018, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,166
- views
-
- 119
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cancer Biology
- Medicine
A doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability.
-
- Cancer Biology
- Chromosomes and Gene Expression
Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.